Variability Of Repolarization Research Articles

Glucose dysregulation and repolarization variability markers are short-term mortality predictors in decompensated heart failure

ObjectiveAs recently reported, elevated fasting glucose plasma level constitutes a risk factor for 30-day total mortality in acutely decompensated chronic heart failure (CHF). Aim of this study was to evaluate the 30-day mortality risk in decompensated CHF patients by fasting glucose plasma level and some repolarization ECG markers.MethodA total of 164 decompensated CHF patients (M/F: 94/71; mean age, 83 ± 10 years) were studied; Tend (Te), QT interval (QT) and 5 min of ECG recordings were obtained, studying mean, SD and normalized index of the abovementioned ECG intervals. These repolarization variables and fasting glucose were analyzed to assess the 30-day mortality risk among these patients.ResultsThirty-day mortality rate was 21%, deceased subjects showed a significant increase in N terminal-pro-brain natriuretic peptide (P < 0.001), higher sensitivity cardiac troponin, fasting glucose, creatinine clearance, QTSD, QTVN, Te mean, TeSD and TeVN than the survivals. Multivariable regression analysis reported that fasting glucose (hazard ratio, 1.59; 95% confidence interval, 1.09–2.10; P < 0.01), Te mean (hazard ratio, 1.03; 95% confidence interval, 1.01–1.05; P < 0.01) and QTSD (hazard ratio, 1.17; 95% confidence interval, 1.01–1.36; P < 0.05) were significantly related to higher mortality risk, whereas only fasting glucose (hazard ratio, 1.84; 95% confidence interval, 1.12–3.02; P < 0.05) and Te mean (hazard ratio, 1.07; 95% confidence interval, 1.02–1.11; P < 0.01) were associated to cardiovascular mortality.ConclusionData suggest that two simple, inexpensive, noninvasive markers, as fasting glucose and Te, were capable to stratify the short-term total and cardiovascular mortality risk in acutely decompensated CHF.

Adrenergic stimulation amplifies the difference in beat-to-beat variability between the scar border zone and remote region

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): KU Leuven BOF-C1 “Blood pressure induced premature ventricular beats as triggers for ventricular arrhythmia in ischemic cardiomyopathy” Background Myocardial infarction (MI) results in a dense scar region surrounded by a heterogeneous region of fibrosis and remodeled myocytes called the border zone (BZ). Beta-adrenergic stimulation results in increased beat-to-beat variability of repolarization (BVR) which could increase spatial heterogeneity and arrhythmia vulnerability. Objective To examine the effect of adrenergic stimulation on the beat-to-beat variability in the BZ, compared to the remote region, using novel methodology for determining spatially dense activation-repolarization intervals. Methods Anterior-septal myocardial infarction (MI) was induced in 10 domestic pigs by 120-minute occlusion of the left anterior descending artery followed by reperfusion. Electro-anatomical mapping was performed after one month. The BZ was defined using contact mapping as the region with bipolar voltage between 0.5 and1.5mV. A non-contact recording of a 64-electrode array was translated to 2048 non-contact electrograms distributed over the LV (EnSite PrecisionTM, St. Jude/Abbott Medical). Electrophysiological recordings were made during baseline and during an isoproterenol (ISO) infusion (incremental doses of 0.01µg/kg until 0.04µg/kg). In each of the 2048 points non-contact electrograms over 25 consecutive beats were processed to determine the BVR using a custom-made algorithm, validated against monophasic action potential recordings. Results During baseline conditions the maximal BVR was increased in the BZ compared to the remote region (BZ: 3.28±0.90 ms vs remote: 2.61±0.67 ms, P=0.002). During ISO infusion the maximal BVR was also increased in the BZ (BZ: 3.55±0.74 ms vs remote: 2.21±0.60 ms, P&amp;lt;0.001). During baseline the BZ exhibited a larger spatial variance of BVR than the remote region (BZ: 0.20±0.11 ms2 vs remote: 0.087±0.055 ms2, P=0.002). During ISO infusion the spatial variance of BVR was larger in the BZ (BZ: 0.23±0.12 ms2 vs remote: 0.083±0.056 ms2, P=0.001). The maximal BVR was not significantly different during baseline and ISO in the BZ, nor the remote region (P&amp;gt;0.05). However, the difference of the maximal BVR between BZ and remote regions was significantly increased during ISO (baseline: 0.67±0.48 ms vs ISO: 1.34±0.49ms, P=0.001). Conclusion The MI BZ showed increased temporal heterogeneity in repolarization that could serve as functional substrate for re-entry. Adrenergic stimulation amplified this vulnerability by increasing the difference in maximal BVR between BZ and remote regions.

Long-Term Endurance Exercise Training Alters Repolarization in a New Rabbit Athlete's Heart Model.

In the present study, the effect of long-term exercise training was investigated on myocardial morphological and functional remodeling and on proarrhythmic sensitivity in a rabbit athlete’s heart model. New-Zealand white rabbits were trained during a 12-week long treadmill running protocol and compared with their sedentary controls. At the end of the training protocol, echocardiography, in vivo and in vitro ECG recordings, proarrhythmic sensitivity with dofetilide (nM) were performed in isolated hearts, and action potential duration (APD) measurements at different potassium concentrations (4.5 and 2 mM) were made in the isolated papillary muscles. Expression levels of the slow component of delayed rectifier potassium current and fibrosis synthesis and degradation biomarkers were quantified. Echocardiography showed a significantly dilated left ventricle in the running rabbits. ECG PQ and RR intervals were significantly longer in the exercised group (79 ± 2 vs. 69 ± 2 ms and 325 ± 11 vs. 265 ± 6 ms, p < 0.05, respectively). The in vivo heart rate variability (HRV) (SD of root mean square: 5.2 ± 1.4 ms vs. 1.4 ± 0.2 ms, p < 0.05) and Tpeak-Tend variability were higher in the running rabbits. Bradycardia disappeared in the exercised group in vitro. Dofetilide tended to increase the QTc interval in a greater extent, and significantly increased the number of arrhythmic beats in the trained animals in vitro. APD was longer in the exercised group at a low potassium level. Real-time quantitative PCR (RT-qPCR) showed significantly greater messenger RNA expression of fibrotic biomarkers in the exercised group. Increased repolarization variability and higher arrhythmia incidences, lengthened APD at a low potassium level, increased fibrotic biomarker gene expressions may indicate higher sensitivity of the rabbit “athlete’s heart” to life-threatening arrhythmias.

EP News: Basic and Translational

Hutchings et al (Circ Res 2021;129:650, PMID 34247494) investigated the mechanisms of the antiarrhythmic effects of phosphodiesterase 5 (PDE5) inhibition in a proarrhythmic sheep model by using the rapidly activating delayed rectifier K+ channel inhibitor dofetilide to induce QT prolongation and arrhythmia. PDE5 inhibition was achieved using acute application of sildenafil, and protein kinase G (PKG) was inhibited with KT5823. PDE5 inhibition reduced beat-to-beat variability of repolarization and suppressed afterdepolarizations, premature ventricular complexes, and torsades de pointes in vivo.

Ventricular depolarization and repolarization variability in children with type 1 diabetes mellitus.

Arrhythmias can be seen as a sign of cardiac autonomic neuropathy in type 1 diabetes mellitus. We aimed to evaluate pulmonary artery pressure, ventricular depolarization and repolarization variability in children with type 1 diabetes mellitus. We investigated 78 children with type 1 diabetes mellitus (mean age 11.6 ± 3.6 years) and 68 age-gender matched healthy children as control group. All type 1 diabetes mellitus patients were divided into three subgroups according to glycated hemoglobin (HbA1c) levels and the duration of disease. Electrocardiogram and transthoracic echocardiograms were performed on both groups. In patients with type 1 diabetes mellitus, there was an elongation in P, Pd, PR, QTc, QTd, QTcd, JT, JTc, JTd, Tp-Te and Tp-Te/QT, Tp-Te/QTc, Tp-Te/JT, Tp-Te/JTc ratios were higher (P < 0.05). In patients with type 1 diabetes mellitus, pulmonary artery pressure was higher than control group (P = 0.001). Prolongation of QTc, thickness of left ventricle end-diastolic diameter and left ventricle posterior wall diameter were higher in the HbA1c ≥9% subgroup. When adjusted for age there was no significant correlation between left ventricle parameters and HbA1c. Atrial conduction delay and impairment of ventricular repolarization were significantly high and there was a predisposition for the development of pulmonary artery hypertension in children with type 1 diabetes mellitus. Poor glycemic control was not a risk factor for propensity of left ventricle hypertrophy and left ventricle dysfunction.

PDE5 Inhibition Suppresses Ventricular Arrhythmias by Reducing SR Ca2+ Content.

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Electrocardiographic Ventricular Repolarization Variables in Children Diagnosed With COVID-19.

Electrocardiographic Ventricular Repolarization Variables in Children Diagnosed With COVID-19.

Short-term variability of repolarization is equally modulated by atrial and (bi)ventricular high rate pacing in patients with an indication for an implantable cardioverter defibrillator

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation Background An increase in temporal dispersion of repolarization, quantified as short-term variability of the QT-interval (STV-QT), precedes ventricular arrhythmias and has therefore been proposed as a marker for monitoring of imminent arrhythmic risk. A reversal of an increased STV by high rate pacing at 100 bpm was anti-arrhythmic in the chronic atrioventricular block dog model susceptible to Torsade de Pointes arrhythmias upon challenge with an IKr-blocker. The objective of the current study was to investigate the physiological modulation of STV by pacing in patients with an indication for an implantable cardioverter defibrillator (ICD), and to compare atrial and ventricular pacing. Methods ECG recordings were obtained with a sampling frequency of 1200 Hz in 10 dual chamber ICD patients and 10 patients with cardiac resynchronization therapy with defibrillation function (CRT-D) during the implantation or replacement. One-minute recordings were made during sinus rhythm (SR), and during pacing at 80 and 100 beats per minute (bpm) from the atrium (AAI), atrium and right ventricle (DDD RVp), and during atrio-biventricular pacing (DDD BiVp). The QT-interval was determined offline with fiducial segment averaging at one minute of each pacing rate, and 31 consecutive beats were used to calculate STV-QT with the following formula: ∑|D(n + 1)-Dn |/(N×√2), where D represents the determinant of repolarization (in this case the QT interval), and N represents the number of beats taken into account minus 1. Results In the patients overall, STV-QT decreased from 1.27 ± 0.38 ms in SR (±58 bpm) to 0.86 ± 0.26 ms* during AAI80, and to 0.68 ± 0.22 ms*† during AAI100 (*p &amp;lt; 0.05 compared to SR, †p &amp;lt; 0.05 compared to 80 bpm). The same decrease was seen during DDD80 RVp (0.81 ± 0.28 ms*) and during DDD100 RVp (0.66 ± 0.22 ms*†) (fig. 1). Additionally, DDD BiVp decreased STV-QT to 0.78 ± 0.20 ms* at 80 bpm and to 0.62 ± 0.19 ms* at 100 bpm in CRT-D patients (fig. 2). Conclusion Pacing at 80 and 100 bpm decreases STV-QT compared to sinus rhythm both in dual chamber ICD patients and CRT-D patients. The modulation of STV-QT is similar during atrial, and atrio- right ventricular and atrio-biventricular pacing. Abstract Figure. Modulation of STV-QT by AAI and DDD RVp

Association Between Left Atrial Volume Index and Ventricular Repolarization Heterogeneity: A Cross-Sectional Study of a Healthy Chinese Population.

BackgroundElectromechanical coupling may play a significant role in the association between abnormal myocardial mechanics and heterogeneity of repolarization. This study sought to assess the potential relationship between the left atrial volume index (LAVI), which is an important marker of cardiac diastolic function, and ventricular repolarization variables, such as the QT interval, Tpeak-to-Tend (Tpe) interval and Tpe/QT ratio, in an apparently healthy Chinese population.MethodsThis was a community-based cross-sectional study conducted in Shenyang, China. A total of 414 healthy subjects aged 35–91 years, including 186 men (44.9%), were enrolled. In addition to performing clinical and laboratory measurements, all subjects underwent comprehensive echocardiography and standard 12-lead electrocardiography. Echocardiographic and electrocardiographic results were analysed separately and in a blinded fashion. Correlation and regression analyses were applied to determine associations.ResultsSubjects were divided into four groups according to quartile of LAVI levels (<16.0, 16.0–18.9, 19.0–22.5 and >22.5 mL/m2). Ventricular repolarization variables, such as QT interval and QTc interval, gradually increased with the progression from low to high LAVI levels (P<0.05). LAVI was positively and significantly correlated with the QT interval, the QTc interval, and the Tpe interval (P<0.01). After adjusting for age and other possible confounders, LAVI showed significant and independent associations with the QT interval and the QTc interval (P<0.001; P=0.003).ConclusionEchocardiographic LAVI is linearly associated with ventricular repolarization variables even in healthy people.

Severe Bradycardia Increases the Incidence and Severity of Torsade de Pointes Arrhythmias by Augmenting Preexistent Spatial Dispersion of Repolarization in the CAVB Dog Model.

IntroductionTorsade de pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog model result from proarrhythmic factors, which trigger TdP and/or reinforce the arrhythmic substrate. This study investigated electrophysiological and arrhythmogenic consequences of severe bradycardia for TdP.MethodsDofetilide (25 μg/kg per 5 min) was administered to eight anesthetized, idioventricular rhythm (IVR) remodeled CAVB dogs in two serial experiments: once under 60 beats per minute (bpm), right ventricular apex paced (RVA60) conditions, once under more bradycardic IVR conditions. Recordings included surface electrocardiogram and short-term variability (STV) of repolarization from endocardial unipolar electrograms. TdP inducibility (three or more episodes within 10 min after start of dofetilide) and arrhythmic activity scores (AS) were established. Mapping experiments in 10 additional dogs determined the effect of lowering rate on STV and spatial dispersion of repolarization (SDR) in baseline.ResultsIVR-tested animals had longer baseline RR-interval (1,403 ± 271 ms) and repolarization intervals than RVA60 animals. Dofetilide increased STV similarly under both rhythm strategies. Nevertheless, TdP inducibility and AS were higher under IVR conditions (6/8 and 37 ± 27 vs. 1/8 and 8 ± 12 in RVA60, respectively, both p < 0.05). Mapping: Pacing from high (128 ± 10 bpm) to middle (88 ± 10 bpm) to experimental rate (61 ± 3 bpm) increased all electrophysiological parameters, including interventricular dispersion, due to steeper left ventricular restitution curves, and intraventricular SDR: maximal cubic dispersion from 60 ± 14 (high) to 69 ± 17 (middle) to 84 ± 22 ms (p < 0.05 vs. high and middle rate).ConclusionIn CAVB dogs, severe bradycardia increases the probability and severity of arrhythmic events by heterogeneously causing electrophysiological instability, which is mainly reflected in an increased spatial, and to a lesser extent temporal, dispersion of repolarization.

Structural and Electrophysiological Changes in a Model of Cardiotoxicity Induced by Anthracycline Combined With Trastuzumab.

BackgroundCombined treatment with anthracyclines (e.g., doxorubicin; Dox) and trastuzumab (Trz), a humanized anti-human epidermal growth factor receptor 2 (HER2; ErbB2) antibody, in patients with HER2-positive cancer is limited by cardiotoxicity, as manifested by contractile dysfunction and arrhythmia. The respective roles of the two agents in the cardiotoxicity of the combined therapy are incompletely understood.ObjectiveTo assess cardiac performance, T-tubule organization, electrophysiological changes and intracellular Ca2+ handling in cardiac myocytes (CMs) using an in vivo rat model of Dox/Trz-related cardiotoxicity.Methods and ResultsAdult rats received 6 doses of either Dox or Trz, or the two agents sequentially. Dox-mediated left ventricular (LV) dysfunction was aggravated by Trz administration. Dox treatment, but not Trz, induced T-tubule disarray. Moreover, Dox, but not Trz monotherapy, induced prolonged action potential duration (APD), increased incidence of delayed afterdepolarizations (DADs) and beat-to-beat variability of repolarization (BVR), and slower Ca2+ transient decay. Although APD, DADs, BVR and Ca2+ transient decay recovered over time after the cessation of Dox treatment, subsequent Trz administration exacerbated these abnormalities. Trz, but not Dox, reduced Ca2+ transient amplitude and SR Ca2+ content, although only Dox treatment was associated with SERCA downregulation. Finally, Dox treatment increased Ca2+ spark frequency, resting Ca2+ waves, sarcoplasmic reticulum (SR) Ca2+ leak, and long-lasting Ca2+ release events (so-called Ca2+ “embers”), partially reproduced by Trz treatment.ConclusionThese results suggest that in vivo Dox but not Trz administration causes T-tubule disarray and pronounced changes in electrical activity of CMs. While adaptive changes may account for normal AP shape and reduced DADs late after Dox administration, subsequent Trz administration interferes with such adaptive changes. Intracellular Ca2+ handling was differently affected by Dox and Trz treatment, leading to SR instability in both cases. These findings illustrate the specific roles of Dox and Trz, and their interactions in cardiotoxicity and arrhythmogenicity.

Short-period temporal repolarization dispersion in subjects with atrial fibrillation and decompensated heart failure.

The association between chronic heart failure (CHF) and permanent atrial fibrillation is very frequent. The repolarization duration was already found predictive for atrial fibrillation. Aim of this study was to evaluate the influence of atrial fibrillation on short period repolarization variables in decompensated CHF patients. We used 5 min ECG recordings to assess the mean, standard deviation (SD), and normalized variance (NV) of the following variables: QT end (QTe), QT peak (QTp), and T peak to T end (Te) in 121 decompensated CHF, of whom 40 had permanent atrial fibrillation, too. We reported also the 30-day mortality. QTpSD (p<.01), TeSD (p<.01), QTpVN (p<.01), and TeVN (p<.01) were higher in the atrial fibrillation than among sinus rhythm CHF subjects. Multivariable logistic analysis selected only TeSD (odd ratio, o.r.: 1.32, 95% confidence interval, c.i.: 1.06-1.65, p: .015) associated with atrial fibrillation. A total of 27 patients died during the 30-days follow-up (overall mortality rate 22%), 7 (18%), and 20 (25%) respectively in the atrial fibrillation and sinus rhythm patients. Furthermore, the following variables were associated to the morality risk: NT-pro Brain Natriuretic Peptide (o.r.: 1.00, 95% c.i.: 1.00-1.00, p: .041), left ventricular end diastolic diameter (o.r.: 0.81, 95% c.i.: 0.67-0.96, p: .010), and Te mean (o.r.: 1.04, 95% c.i.: 1.02-1.09, p: .012). In decompensated CHF subjects, Te mean seems be associated to mortality and TeSD to the permanent atrial fibrillation. We could hypothesize that, during severe CHF, the multi-level ionic CHF channel derangement could be critical in influencing these non-invasive markers. (ClinicalTrials.gov number, NCT04127162).

Electric Field-Based Dense Spatial Analysis of Unipolar Electrograms to Map Regional Activation-Repolarization Intervals

Objective: We wanted to develop a new method for processing dense spatially sampled unipolar electrograms, that yields physiological spatial distributions in activation-repolarization intervals.Background: Spatial heterogeneity in repolarization plays an important role in genesis and sustainment of cardiac arrhythmias. Reliable determination of repolarization times at high resolution on electrograms remains a difficult task. Methods: The new method describes the electrical activity on the heart's surface in terms of a physical electric field (E-field). Activation and repolarization times are calculated using an amplitude weighted average on QRS and T-waves. Activation-recovery intervals (ARI) obtained with this E-field method were validated against action potential durations (APD90) from monophasic action potential measurements. Relevance of the method was shown by calculating dense spatial distributions of beat-to-beat variability of repolarization (BVR) in myocardial infarction (MI).Results: E-field waveforms were more spatially homogeneous than the unipolar electrograms. The ARI strongly correlated with the APD90 (r2=0.94; p<0.001). Continuous activation and repolarization patterns were obtained, and the method removes non-physiological sharp spatial gradients obtained by currently adopted methods. Spatial BVR analysis revealed an increase in maximum BVR, spatial variance of BVR and spatial gradient of BVR in the border zone versus remote region of MI (all p<0.01). All BVR values were in pathophysiological range as described in other studies.Conclusion: The E-field method allows for a reliable determination of activation and repolarization times over the whole left ventricle. The new methodology confirmed that the border zone of myocardial infarction is a region with patches of increased variability of repolarization.

Measures of repolarization variability predict ventricular arrhythmogenesis in heptanol-treated Langendorff-perfused mouse hearts.

BackgroundTime-domain and non-linear methods can be used to quantify beat-to-beat repolarization variability but whether measures of repolarization variability can predict ventricular arrhythmogenesis in mice have never been explored.MethodsLeft ventricular monophasic action potentials (MAPs) were recorded during constant right ventricular 8 ​Hz pacing in Langendorff-perfused mouse hearts, in the presence or absence of the gap junction and sodium channel inhibitor heptanol (0.1, 0.5, 1 or 2 ​mM).ResultsUnder control conditions, mean action potential duration (APD) was 39.4 ​± ​8.1 ​ms. Standard deviation (SD) of APDs was 0.3 ​± ​0.2 ​ms, coefficient of variation was 0.9 ​± ​0.8% and the root mean square (RMS) of successive differences in APDs was 0.15 ​± ​0.14 ​ms. Poincaré plots of APDn+1 against APDn revealed ellipsoid morphologies with a SD along the line-of-identity (SD2) to SD perpendicular to the line-of-identity (SD1) ratio of 4.6 ​± ​2.1. Approximate and sample entropy were 0.61 ​± ​0.12 and 0.76 ​± ​0.26, respectively. Detrended fluctuation analysis revealed short- and long-term fluctuation slopes of 1.49 ​± ​0.27 and 0.81 ​± ​0.36, respectively. Heptanol at 2 ​mM induced ventricular tachycardia in five out of six hearts. None of the above parameters were altered by heptanol during which reproducible electrical activity was observed (KW-ANOVA, P ​> ​0.05). Contrastingly, SD2/SD1 decreased to 2.03 ​± ​0.41, approximate and sample entropy increased to 0.82 ​± ​0.12 and 1.45 ​± ​0.34, and short-term fluctuation slope decreased to 0.82 ​± ​0.19 during the 20-s period preceding spontaneous ventricular tachy-arrhythmias (n ​= ​6, KW-ANOVA, P ​< ​0.05).ConclusionMeasures of repolarization variability, such as SD2/SD1, entropy, and fluctuation slope are altered preceding the occurrence of ventricular arrhythmogenesis in mouse hearts. Changes in these variables may allow detection of impending arrhythmias for early intervention.

High rate pacing guided by short-term variability of repolarization prevents imminent ventricular arrhythmias autonomically by an ICD

Abstract Background The anesthetized, chronic complete atrioventricular block (CAVB) dog model allows reproducible inducibility of Torsade de Pointes (TdP) arrhythmias due to ventricular remodeling and after a challenge with an IKr-blocker. High rate pacing (HRP) prevents ventricular arrhythmias, but has long-term detrimental effects on cardiac function when applied continuously. Temporal dispersion of repolarization, quantified as short-term variability (STV), increases prior to ventricular arrhythmias and has been proposed as a marker to guide HRP. Purpose A proof-of-principle study to show STV determined automatically and in real-time by an ICD can guide HRP to prevent imminent ventricular arrhythmias. Methods Eight CAVB dogs were implanted with an ICD (Medtronic, lead in the right ventricular (RV) apex), with software to automatically determine STV online (STV-ICD). STV was determined from the activation recovery interval (ARI) of 31 consecutive beats with the formula: STV = Σ|ARI(n+1) − ARI(n)|/(N*√2). The CAVB dogs were challenged twice with dofetilide (0.025 mg/kg i.v. in 5 minutes or until the first TdP). In the first experiment, the individual STV-ICD threshold was determined prior to the first arrhythmic event and programmed into the ICD. In a serial experiment, HRP was initiated automatically once the STV-ICD threshold was reached, by gradually increasing the heart rate to 100 bpm. Occurrence of TdPs was monitored for 10 minutes from the start of dofetilide infusion in both experiments. During HRP, STV was measured offline from RV electrograms (EGM) and left ventricular (LV) monophasic action potential durations (MAPD) (STV-offline). Results During the inducibility experiment, 8/8 dogs had repetitive TdPs and STV-ICD increased from 0.96±0.42 to 2.10±1.26 ms* (*p&amp;lt;0.05). During the prevention experiment, all dogs reached the STV threshold. HRP decreased STV-offline from 2.02±1.12 to 0.78±0.28 ms*, which was accompanied by prevention of TdPs in 7/8 dogs* (Figure 1). Conclusion Temporal dispersion of repolarization, quantified as STV, can guide HRP automatically by an ICD to prevent ventricular arrhythmias. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation Public Private Partnership

Time- and frequency-domain analysis of repolarization phase during recovery from exercise in healthy subjects.

Recently, data from temporal dispersion of myocardial repolarization analysis have gained a capital role in the sudden cardiac death risk stratification. Aim of this study was to evaluate the influence of heart rate, autonomic nervous system, and controlled breathing on different myocardial repolarization markers in healthy subjects. Myocardial repolarization dispersion markers from short-period (5 minutes) electrocardiogram (ECG) analysis (time and frequency domain) have been obtained in 21 healthy volunteers during the following conditions: free breathing (rest); controlled breathing (resp); the first 5 minutes of postexercise recovery phases (exercisePeak ), maximum sympathetic activation; and during the second 5 minutes of postexercise recovery phases (exerciseRecovery ), intermediate sympathetic activation. Finally, we analyzed the whole repolarization (QTe), the QT peak (QTp), and T peak - T end intervals (Te). During the exercisePeak , major part of repolarization variables changed in comparison to the rest and resp conditions. Particularly, QTe, QTp, and Te standard deviations (QTeSD , QTpSD , and TeSD ); variability indexes (QTeVI and QTpVI), normalized variances (QTeVN, QTpVN, and TeVN); and the ratio between short-term QTe, QTp, and Te variability RR (STVQTe/RR , STVQTp/RR, and STVTe/RR ) increased. During exerciseRecovery , QTpSD (P<.05), QTpVI (P<.05), QTeVN (P<.05), QTpVN (P<.001), TeVN (P<.05), STVQTe/RR (P<.05), STVQTp/RR (P<.001), and STVTe/RR (P<.001) were significantly higher in comparison to the rest. The slope between QTe (0.24 ± 0.06) or QTp (0.17 ± 0.06) and RR were significantly higher than Te (0.07 ± 0.06, P<.001). Heart rate and sympathetic activity, obtained during exercise, seem able to influence the time domain markers of myocardial repolarization dispersion in healthy subjects, whereas they do not alter any spectral components.

Evaluation of a Fully Automatic Measurement of Short-Term Variability of Repolarization on Intracardiac Electrograms in the Chronic Atrioventricular Block Dog

Background: Short-term variability (STV) of repolarization of the monophasic action potential duration (MAPD) or activation recovery interval (ARI) on the intracardiac electrogram (EGM) increases abruptly prior to the occurrence of ventricular arrhythmias in the chronic AV-block (CAVB) dog model. Therefore, this parameter might be suitable for continuous monitoring of imminent arrhythmias using the EGM stored on an implanted device. However, 24/7 monitoring would require automatic STVARI measurement by the device.Objective: To evaluate a newly developed automatic measurement of STVARI for prediction of dofetilide-induced torsade de pointes (TdP) arrhythmias in the CAVB-dog.Methods: Two retrospective analyses were done on data from recently performed dog experiments. (1) In seven anesthetized CAVB-dogs, the new automatic STVARI method was compared with the gold standard STVMAPD at baseline and after dofetilide administration (0.025 mg/kg in 5 min). (2) The predictive value of the automatic method was compared to currently used STVARI methods, i.e., slope method and fiducial segment averaging (FSA) method, in 11 inducible (≥3 TdP arrhythmias) and 10 non-inducible CAVB-dogs.Results: (1) The automatic measurement of STVARI had good correlation with STVMAPD (r2 = 0.89; p < 0.001). Bland-Altman analysis showed a small bias of 0.06 ms with limits of agreement between −0.63 and 0.76 ms. (2) STVARI of all three methods was significantly different between inducible and non-inducible dogs after dofetilide. The automatic method showed the highest predictive performance with an area under the ROC-curve of 0.93, compared to 0.85 and 0.87 of the slope and FSA methods, respectively. With a threshold of STV set at 1.69 ms, STVARI measured with the automatic method had a sensitivity of 0.91 and specificity of 0.90 in differentiating inducible from non-inducible subjects.Conclusion: We developed a fully-automatic method for measurement of STVARI on the intracardiac EGM that can accurately predict the occurrence of ventricular arrhythmias in the CAVB-dog. Future integration of this method into implantable devices could provide the opportunity for 24/7 monitoring of arrhythmic risk.

Torsadogenic potential of a novel remyelinating drug clemastine for multiple sclerosis assessed in the rabbit proarrhythmia model

We assessed the torsadogenic effects of a novel remyelinating drug clemastine for multiple sclerosis using an in vivo proarrhythmia model of acute atrioventricular block rabbit, since the drug has been demonstrated to suppress the human ether-á-go-go related gene (hERG) K+ channels. Bradycardia was induced by atrioventricular node ablation in isoflurane-anesthetized New Zealand White rabbits (n = 5), and the ventricle was electrically driven at 60 beats/min throughout the experiment, except when extrasystoles appeared. Intravenous administration of clinically relevant dose of 0.03 mg/kg of clemastine and 10-times higher dose of 0.3 mg/kg hardly affected the QT interval or duration of the monophasic action potential (MAP) of the ventricle. Additional administration of clemastine at 3 mg/kg significantly increased the QT interval, MAP duration and the short-term variability of repolarization. Meanwhile, the premature ventricular contractions with R on T phenomenon were observed in 3 out of 5 animals, and torsades de pointes arrhythmias were detected in 1 out of 5 animals. These results suggest that the torsadogenic potential of clemastine is obviously observed in the acute atrioventricular block rabbit, which will not appear within the prescribed dose for multiple sclerosis.

High-rate pacing guided by short-term variability of repolarization prevents imminent ventricular arrhythmias automatically by an implantable cardioverter-defibrillator in the chronic atrioventricular block dog model

The anesthetized, complete chronic atrioventricular block (CAVB) dog model allows reproducible inducibility of torsades de pointes (TdP) arrhythmias due to ventricular remodeling and after a challenge with an IKr blocker. High-rate pacing (HRP) prevents ventricular arrhythmias but has long-term detrimental effects on cardiac function when applied continuously. Temporal dispersion of repolarization, quantified as short-term variability (STV), increases before ventricular arrhythmias and has been proposed as a marker to guide HRP. The purpose of this proof-of-principle study was to show that automatically determined STV can guide HRP to prevent imminent ventricular arrhythmias. Eight CAVB dogs were implanted with an implantable cardioverter-defibrillator (ICD) with software to automatically determine STV (STVICD) in real time. During HRP, STV was measured offline from right ventricular (RV) electrograms (EGMs) and left ventricular (LV) monophasic action potential durations (MAPDs) (STVRV,EGM/LV,MAPD). The CAVB dogs were challenged twice with dofetilide (0.025 mg/kg intravenously over 5 minutes or until the first TdP). In experiment 1, the individual STVICD threshold before the first arrhythmic event was determined and programmed into the ICD. In experiment 2, HRP with 100 bpm was initiated automatically once the STVICD threshold was reached. In experiment 1, 8 of 8 dogs had repetitive TdP, and STVICD increased from 0.96 ± 0.42 ms to 2.10 ± 1.26 ms (P <.05). In experiment 2, all dogs reached the STV threshold. HRP decreased STVRV,EGM/LV,MAPD from 2.02 ± 1.12 ms to 0.78 ± 0.28 ms, which was accompanied by prevention of TdP in 7 of 8 dogs. STV can guide HRP automatically by an ICD to prevent ventricular arrhythmias.

Evaluation of electrocardiographic ventricular repolarization variables in patients with newly diagnosed COVID-19

IntroductionCoronavirus disease 2019 (COVID-19) is a newly recognized infectious disease that has spread rapidly. COVID-19 has been associated with a number of cardiovascular complications, including arrhythmias. The mechanism of ventricular arrhythmias in patients with COVID-19 is uncertain. The aim of the present study was to evaluate the ventricular repolarization by using the Tp-e interval, QT dispersion, Tp-e/QT ratio, and Tp-e/QTc ratio as candidate markers of ventricular arrhythmias in patients with newly diagnosed COVID-19. In addition, the relationship between the repolarization parameters and the CRP (C-reactive protein) was investigated. Methods75 newly diagnosed COVID-19 patients, 75 age and sex matched healthy subjects were included in the study between 20th March 2020 and 10th April 2020. The risk of ventricular arrhythmias was evaluated by calculating the electrocardiographic Tp-e and QT interval, Tp-e dispersion, corrected QT(QTc), QT dispersion (QTd), corrected QTd, Tp-e/QT and Tp-e/QTc ratios. CRP values were also measured in patients with newly diagnosed COVID-19. ResultsTp-e interval (80.7 ± 4.6 vs. 70.9 ± 4.8; p < .001), Tp-e / QT ratio (0.21 ± 0.01 vs. 0.19 ± 0.01; p < .001) and Tp-e/QTc ratio (0.19 ± 0.01 vs.0.17 ± 0.01; p < .001) were significantly higher in patients with newly diagnosed COVID-19 than the control group. There was a significant positive correlation between Tp-e interval, Tp-e/QTc ratio and CRP in patients with newly diagnosed COVID-19 (rs = 0.332, p = .005, rs = 0.397, p < .001 consecutively). During their treatment with hydroxychloroquine (HCQ), azithromycin and favipiravir, ventricular tachycardia episodes were observed in in two COVID-19 patients during their hospitalization in the intensive care unit. ConclusionOur study showed for the first time in literature that the Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio, which are evaluated electrocardiographically in patients with newly diagnosed COVID-19, were prolonged compared with normal healthy individuals. A positive correlation was determined between repolarization parameters and CRP. We believe that pre-treatment evaluation of repolarization parameters in newly diagnosed COVID-19 would be beneficial for predicting ventricular arrhythmia risk.